1

Examples in Stakeholder

Collaboration for Risk Assessment

ScienceAndrew Maier

Jacqueline PattersonMichael Dourson

2

Presentation Overview A few words on the importance of A few words on the importance of

collaborationcollaboration Some examples of collaborative processesSome examples of collaborative processes Take home message: Take home message:

We are all committed to protecting public We are all committed to protecting public health, although the issues are frequently health, although the issues are frequently complex they can often be solved through complex they can often be solved through collaborative approaches (we’ll get collaborative approaches (we’ll get farther faster).farther faster).

3

Toxicology Excellence for Risk Toxicology Excellence for Risk AssessmentAssessment

About About TERA:TERA: A non-profit, 501(c)(3) corporation A non-profit, 501(c)(3) corporation Mission to protect public healthMission to protect public health Founded in 1995 with a current technical staff of Founded in 1995 with a current technical staff of

12 and several visiting scientists and associates. 12 and several visiting scientists and associates. Completes roughly 50 technical projects per year Completes roughly 50 technical projects per year

for government and industry sponsors (strives for for government and industry sponsors (strives for 50:50 balance) in areas including developing 50:50 balance) in areas including developing chemical assessments, risk methods development, chemical assessments, risk methods development, and peer review and consultation; provides and peer review and consultation; provides ITERITER databasedatabase

Focus on – solving risk science issues through 1) Focus on – solving risk science issues through 1) technology leadership, 2) building bridges among technology leadership, 2) building bridges among stakeholder groupsstakeholder groups

http://www.tera.orghttp://www.tera.org

4

Key Benefits of Key Benefits of CollaborationCollaboration

Promotes science-based decision making to protect Promotes science-based decision making to protect human health by ensuring all key data and ideas are human health by ensuring all key data and ideas are fully consideredfully considered

Enhances harmonization and consistency in risk Enhances harmonization and consistency in risk assessments thru an open, transparent, multi-assessments thru an open, transparent, multi-stakeholder approach that ultimately foster stakeholder approach that ultimately foster harmonization and information sharingharmonization and information sharing

Makes use of groups of experts that are normally not Makes use of groups of experts that are normally not available within a single organizationavailable within a single organization

Shares costs and human resources among multiple Shares costs and human resources among multiple stakeholders to increase output for the broader risk stakeholders to increase output for the broader risk communitycommunity

This can all be achieved while allowing groups to This can all be achieved while allowing groups to control their own process and can receive broad control their own process and can receive broad acceptance with thoughtful management of biasesacceptance with thoughtful management of biases

5

Benefits of CollaborationBenefits of Collaboration

Many international initiatives reflect Many international initiatives reflect desire of risk science community for desire of risk science community for increasing partnershipsincreasing partnerships SRA Europe – June 2007 : “Building SRA Europe – June 2007 : “Building

Bridges Issues for Future Risk Bridges Issues for Future Risk Research”Research”

International Programme for Chemical International Programme for Chemical Safety (IPCS) Harmonization ProjectSafety (IPCS) Harmonization Project

6

Harmonization

Harmonization is not standardizationHarmonization is not standardization Understanding the methods and practices Understanding the methods and practices

used by various organizationsused by various organizations Developing confidence in and acceptance Developing confidence in and acceptance

of assessments using different approachesof assessments using different approaches Willingness to work toward a convergence Willingness to work toward a convergence

of methodologies as long-term goalof methodologies as long-term goal

7

Does similar Does similar momentum for momentum for

collaboration exist collaboration exist in U.S.? in U.S.?

Yes - we think so.Yes - we think so.

8

A Few Examples of Collaboration

Peer involvement processes - Voluntary Peer involvement processes - Voluntary Children’s Chemical Evaluation ProgramChildren’s Chemical Evaluation Program

Genotoxicity MOA Cooperative Research Genotoxicity MOA Cooperative Research and Development Agreement (CRADA)and Development Agreement (CRADA)

Alliance for Risk Assessment (Alliance for Risk Assessment (ARAARA))

9

Peers:Experts of equal standing

as the authors

Peer Involvement:Gathering advice and

review on risk assessment products from peers

Peer Consultation: a formal or informalprocess to gather expert peer opinion and advice on a work product

Peer Review:a formal, external,and independent review of an intended final work product

Peer Input:soliciting information,data, or opinion,generally at an early stage of a work product’s development

Peer Involvement

10

Development Stage Type of Peer Involvement

Problem Formulation, Issue Identification, and Data Gathering

Peer Input Data requests Workshops, Meetings , informal or formal Informal discussions Expert Elicitation to fill data gaps or address uncertainties

Draft Work Product Peer Consultation Requests for written comments or review Panel meetings or conference calls On single issues or entire work product

Final Draft Work ProductFinal Draft Work Product Peer ReviewWritten or letter review Panel meetings or conference calls On near final work product

11

VCCEPVCCEP A joint effort of multiple stakeholders:A joint effort of multiple stakeholders:

Companies that manufacture, import, or use chemicals Companies that manufacture, import, or use chemicals covered by TSCAcovered by TSCA

EPA OPPTEPA OPPT Children’s health groupsChildren’s health groups Chemical testing interest groupsChemical testing interest groups Animal welfare groupsAnimal welfare groups

Purpose - to enable the public to better understand Purpose - to enable the public to better understand the potential health risks to children associated with the potential health risks to children associated with certain chemical exposure certain chemical exposure

Industry prepares assessments of hazard, exposure Industry prepares assessments of hazard, exposure and risk to children and recommends data gaps and and risk to children and recommends data gaps and data needs. data needs.

Assessments reviewed by diverse and balanced panels Assessments reviewed by diverse and balanced panels under under TERATERA peer consultation program. Core and peer consultation program. Core and ad ad hochoc panel members used. panel members used.

EPA uses PC report as input as it decides whether EPA uses PC report as input as it decides whether further testing is needed.further testing is needed.

12

TERA’sTERA’s Role in VCCEP Role in VCCEP Under a Cooperative Agreement from EPA, Under a Cooperative Agreement from EPA,

TERATERA is designing, developing and managing a is designing, developing and managing a Peer Consultation process to serve as a public Peer Consultation process to serve as a public scientific forum. One of the major activities scientific forum. One of the major activities undertaken by undertaken by TERATERA under this agreement is under this agreement is the VCCEP. the VCCEP.

TERATERA’s primary role in managing the VCCEP ’s primary role in managing the VCCEP Peer Consultation is to ensure that it is a Peer Consultation is to ensure that it is a rigorous, science-based process for reviewing rigorous, science-based process for reviewing chemical assessments that stakeholders chemical assessments that stakeholders recognize as impartial and of significant recognize as impartial and of significant technical merit and value.technical merit and value.

TERATERA selects panelists, conducts all aspects of selects panelists, conducts all aspects of the meetings, and prepares the reportsthe meetings, and prepares the reports..

13

Using Peer Involvement to Using Peer Involvement to Advance Resolution of Advance Resolution of

Pesticide IssuesPesticide Issues Industry develops document or work Industry develops document or work

product product Vetted by Independent Peer Consultation Vetted by Independent Peer Consultation

Panel in an open and transparent fashionPanel in an open and transparent fashion Shared with EPA and others for their Shared with EPA and others for their

potential use as input to support decision-potential use as input to support decision-makingmaking

A supplement to EPA SAP for appropriate A supplement to EPA SAP for appropriate issuesissues

Captan cancer reclassification is an Captan cancer reclassification is an example of such an application of the example of such an application of the processprocess

14

Captan Tumor Mode of Captan Tumor Mode of ActionAction

A Success Story in Stakeholder InvolvementA Success Story in Stakeholder Involvement EPA’s cancer assessment for Captan was based on EPA’s cancer assessment for Captan was based on

EPA’s 1986 Cancer Guidelines.EPA’s 1986 Cancer Guidelines. EPA OPP indicated they were not planning a re-EPA OPP indicated they were not planning a re-

evaluation, but would consider an independently evaluation, but would consider an independently reviewed reassessment.reviewed reassessment.

The Captan Task Force sponsored an updated The Captan Task Force sponsored an updated analysis, which supported a non-linear mode of analysis, which supported a non-linear mode of action.action.

TERATERA convened an independent peer review panel. convened an independent peer review panel. The panel provided several recommendations, but The panel provided several recommendations, but agreed with the nonlinear mode of action.agreed with the nonlinear mode of action.

EPA OPP accepted the conclusions of the EPA OPP accepted the conclusions of the independent peer review.independent peer review.

See: See: www.tera.org/peer/CAPTAN/CAPTANWelcome.htmwww.tera.org/peer/CAPTAN/CAPTANWelcome.htm

15

A NEW STRATEGY TO IDENTIFY CHEMICALS A NEW STRATEGY TO IDENTIFY CHEMICALS THAT ARE MUTAGENS AND CARCINOGENS BUT THAT ARE MUTAGENS AND CARCINOGENS BUT NOT NECESSARILY MUTAGENIC CARCINOGENSNOT NECESSARILY MUTAGENIC CARCINOGENS

NCTRMartha Moore, Robert Heflich

TERALynne Haber, Mike Dourson

ENVIRON Annette Shipp, Robinan GentryAnnette Shipp, Robinan Gentry

Bruce Allen ConsultingBruce Allen Consulting Bruce AllenBruce Allen

University of Arkansas for Medical SciencesUniversity of Arkansas for Medical Sciences Ralph Kodell

Disclaimer: Not Official FDA Policy

16

MOA CRADAMOA CRADA

Stakeholder identifies chemical for which Stakeholder identifies chemical for which reassessment of Cancer MOA is neededreassessment of Cancer MOA is needed

NCTR conducts NCTR conducts in vivoin vivo mutagenicity/ mutagenicity/ tumorigenicity assaytumorigenicity assay

NCTR, NCTR, TERATERA, Environ evaluate mutation , Environ evaluate mutation frequency and tumor data to test frequency and tumor data to test concordance with Hill criteria (dose-concordance with Hill criteria (dose-response and temporal response)response and temporal response)

Analysis provided to EPA to consider in Analysis provided to EPA to consider in weight of evidence for cancer reassessmentsweight of evidence for cancer reassessments

17

Design for Design for in vivoin vivo Mutation Mutation Studies Addressing Cancer MOAStudies Addressing Cancer MOA

Use transgenic model that will detect point Use transgenic model that will detect point mutations (base pair subs, frameshifts, very small mutations (base pair subs, frameshifts, very small deletions/insertions)deletions/insertions) Big Blue transgenic model Big Blue transgenic model

Chronic treatment (up to 12 months) modeled on Chronic treatment (up to 12 months) modeled on the tumor bioassaythe tumor bioassay

Same species/strain as cancer studySame species/strain as cancer study Same exposure route as cancer studySame exposure route as cancer study Detection of mutation in the target tissue(s)Detection of mutation in the target tissue(s) Multiple doses (6 or 7) based on tumor data--Multiple doses (6 or 7) based on tumor data--

Enough doses to adequately characterize the dose Enough doses to adequately characterize the dose responseresponse

Evaluate mutation, toxicity, cell proliferation at 28 Evaluate mutation, toxicity, cell proliferation at 28 days, 3, 6, 9, 12 months (Time-to-mutation)days, 3, 6, 9, 12 months (Time-to-mutation)

18

Riddelliine: Dose Response Concordance

Fitted dose-response curves for MF and cancer incidence on a probabilityscale. Cancer dose-response ( ) is based on fitting a multistagemodel. Two probability dose-responses for MF are shown, resultingfrom different assumptions regarding the background rate of response(0.058 or 0.01).

19

DCA: Dose Response Concordance

Fitted dose-response curves for MF and cancer incidence on a probabilityscale. Cancer dose-response ( ) is based on fitting a multistagemodel. Two probability dose-responses for MF are shown, resulting fromdifferent assumptions regarding the background rate of response(0.26, -- -- --; or 0.01, -------).

20

Alliance for Risk Alliance for Risk Assessment Assessment

((ARAARA))A process toA process to facilitate communication and collaboration toward

development of useful and timely risk science products.

21

Alliance for Risk Assessment Alliance for Risk Assessment

((ARAARA)) States,

Fed. Agencies, Public Interests,

Industry

Initiation ofRisk Issue

Document Draft

PeerReviews

Release toPublic

Hazard AssessmentNotification

System (HANS)

Risk DocumentDevelopment

Peer Consult

Risk ResearchAnd Tools

ITER

Training andCertification

Peer Review

Non-profitCollaborators

Alliance “Menu” OptionsStakeholder Process

RiskCommunication

SteeringCommittee

22

ARA Work FlowARA Work Flow

Federal Agencies, Industry

Hazard AssessmentNotification

System (HANS)

ITER

SteeringCommittee

States, Tribes,

Env. NGOs

TERA andNon-Profit

Collaborators

Unfunded Project Requests

Funded Projects

23

ARA Funds FlowARA Funds Flow

Federal Agencies ARAProcess

IndustryFundedProjects

Unfunded

Projects

Federal Funds

Federal Funds

Contracts

Contracts

100 Risk Issues per

Year by Year 5

24

The The ARAARA Sand Box Sand Box The The ARAARA seeks collaboration building and seeks collaboration building and

there is a role for all players…there is a role for all players… Players: federal government, local Players: federal government, local

government, tribes, industry, for-profit government, tribes, industry, for-profit consultants, NGOs.consultants, NGOs.

Roles: Roles: users - use of work products, use of information users - use of work products, use of information

exchange, work product vetting, exchange, work product vetting, experts assisting other (e.g., peer review panel experts assisting other (e.g., peer review panel

member) member) developing work productsdeveloping work products Steering Committee membershipSteering Committee membership

25

ARA Steering CommitteeARA Steering Committee Provides advice to ARA Partners on Provides advice to ARA Partners on

mission- relatedness, project mission- relatedness, project prioritization, Conflict of Interest, prioritization, Conflict of Interest,

Scientists:Scientists: 2 States2 States 1 Tribe1 Tribe 1 Env. Group1 Env. Group 2 Federal2 Federal 1 Industry1 Industry 1 Academic1 Academic 2 ARA Partners2 ARA Partners

26

Why Would Diverse Why Would Diverse Groups Provide Funding?Groups Provide Funding?

The Alliance for Risk AssessmentThe Alliance for Risk Assessment (ARA) (ARA) mission…mission… Aligns with many public health goals.Aligns with many public health goals. Provides value as a timely resource for technical products Provides value as a timely resource for technical products

with enhanced credibility.with enhanced credibility. Allows Stakeholder input – e.g., via involvement in Science Allows Stakeholder input – e.g., via involvement in Science

Steering Committee, as participants in technical panels.Steering Committee, as participants in technical panels. Gives an opportunity for harmonizing risk values and Gives an opportunity for harmonizing risk values and

methods – which eases burden for stakeholders that must methods – which eases burden for stakeholders that must meet requirements in multiple constituencies.meet requirements in multiple constituencies.

Over the years nonprofit corporations have demonstrated the Over the years nonprofit corporations have demonstrated the concept can work [e.g., peer consultation with Voluntary concept can work [e.g., peer consultation with Voluntary Children’s Chemical Evaluation Program (VCCEP) of EPA].Children’s Chemical Evaluation Program (VCCEP) of EPA].

NLM & NLM & TERATERA have success in building have success in building ITERITER; ~200,000 hits ; ~200,000 hits per year demonstrates likely value of per year demonstrates likely value of ARAARA

Aligns with stated needs of stakeholders – e.g., Environmental Aligns with stated needs of stakeholders – e.g., Environmental Council of States (ECOS) call for harmonized process.Council of States (ECOS) call for harmonized process.

27

ITER Daily Users

0

50

100

150

200

250

300

350

400

450

01/3 01/4 02/1 02/2 02/3 02/4 03/1 03/2 03/3 03/4 04/1 04/2 04/3 04/4 05/1 05/2 05/3 05/4 06/1 06/2

Year and Quarter

Nu

mb

er o

f U

sers

per

Day

National Library of Medicine

NSF Intl & IARC

IRIS, ATSDR & Health Canada

RIVM

Independent Values

28

NLM’s ToxnetNLM’s Toxnet

29

Does Stakeholder Does Stakeholder Interest Exist?Interest Exist?

In exploring the needs for this In exploring the needs for this ARAARA, , TERATERA has provided has provided briefing and/or received input from many potential briefing and/or received input from many potential stakeholders (over 100 individuals) Including:stakeholders (over 100 individuals) Including: 30 States30 States 2 Tribes2 Tribes 4 Environmental NGO’s4 Environmental NGO’s 30 Industry groups30 Industry groups 6 U.S. Federal Agencies6 U.S. Federal Agencies 4 Countries4 Countries

Feed back has been positive. Suggestions have led to Feed back has been positive. Suggestions have led to refinements in the proposed refinements in the proposed ARAARA. Nearly all . Nearly all responding contacts have encouraged moving forward.responding contacts have encouraged moving forward.

Diverse groups are beginning to provide funding or Diverse groups are beginning to provide funding or suggest projectssuggest projects

30

Does This Effort Does This Effort Duplicate Current Duplicate Current Federal Efforts?Federal Efforts? This effort does not duplicate ATSDR MRLs, EPA IRIS, FDA This effort does not duplicate ATSDR MRLs, EPA IRIS, FDA

ADIs, Health Canada TDIs or RIVM TOCs.ADIs, Health Canada TDIs or RIVM TOCs.

To the contrary,To the contrary, ARA ARA shares resources to avoid duplication shares resources to avoid duplication because:because: It does not replace individual regulatory It does not replace individual regulatory

processes; processes; ARAARA users tap in as appropriate. users tap in as appropriate. Many risk values/issues will never be worked by Many risk values/issues will never be worked by

federal groups.federal groups. Current federal approaches have resource Current federal approaches have resource

limitations; thus, new chemicals addressed limitations; thus, new chemicals addressed without duplicate effort.without duplicate effort.

Update of older values can benefit federal groups Update of older values can benefit federal groups as one technical input to internal deliberations.as one technical input to internal deliberations.

ARAARA goes beyond risk values/issues – it is also a goes beyond risk values/issues – it is also a shared resource for training and data shared resource for training and data communication.communication.

31

ARAARA Supports Existing Supports Existing Risk ValuesRisk Values

Provides guidance Provides guidance for sources of for sources of toxicity information toxicity information that may be used in that may be used in performing human performing human health risk health risk assessmentsassessments

ITERITER can can supplement existing supplement existing toxicity datatoxicity data

ARAARA can provide can provide Tier III valuesTier III values

EPA OSWER Directive 9285.7-53

32www.allianceforrisk.org

33

SummarySummary

We are all committed to protecting We are all committed to protecting public health, although the issues are public health, although the issues are frequently complex they can often be frequently complex they can often be solved through collaborative solved through collaborative approaches (we’ll get farther faster).approaches (we’ll get farther faster).

34

Collaboration is PowerfulCollaboration is Powerful

35

Questions?Questions?